Well, good morning, everybody, and thank you once again for joining us at the fifth Annual Oncology Innovation Summit. I'm Yaron Werber from the biotech team at TD Cowen, and it's a great pleasure to moderate the next session with Relay Therapeutics, with my colleagues, my colleague, Jeanna Hahn. With us today, Don Bergstrom, President of R&D, and Pete Rahmer, our Chief Corporate Development Officer. Gentlemen, thanks so much for joining us. We appreciate it. Thank you for having us, Yaron. So we know lots to talk about, both on the PI3K program and the FGFR2. But maybe first, let's talk about on June sixth, you're gonna be doing an event, you know, live in New York City, for those who are joining live. And I believe the invite talked about both discussing the Dynamo platform and also, something along the lines of upcoming programs. Can you maybe just elaborate a little bit on the purpose for the day and what you might cover? Yes, absolutely. You know, it's been a while since we've disclosed a new innovative program, target for coming out of the Dynamo platform. And so we're very excited to be able to have that opportunity coming up a little over a week from now. You know, last year, we guided to disclosing new target or targets this year, and so this will be the forum in which we do that. And the nature of these, of the programs that we'll disclose are either to come from our genetic disease portfolio or our oncology portfolio. And the goal of the programs that we disclose will be to be either best-in-class or first-in-class programs. And so they'll kind of have the look and feel of 2608, so our PI3K alpha mutant selective franchise, or 4008, the FGFR2 inhibitor. So trying to... They'll be programs where we're solving problems that have been very difficult, if not, you know, not traditional tools and techniques. Within those stories, we'll show you how we use the Dynamo platform to produce these novel programs. As you're thinking about when you typically disclose programs, they're usually, what, about a year away from IND? Is that sort of been the practice in the past? In and around then, yeah. We kind of, you know, in and around the line of sight on DC development candidate. So, yeah, that's still fair. I think the way it is when we disclose a new program, we wanna be able to guide to a clinical start, and so, you know, a year or so out. Okay. Okay, and it sounds like it's gonna be programs with an S at the end, not, not a program, not a single. That's correct. Okay. Got it. Okay, will you talk about the Dynamo platform as well, or mostly kind of what the next programs are gonna be? The key focus will be on... And, you know, like, one of the things that you've always heard us say is, these tech-enabled platforms or AI-enabled or platforms, however, the verbiage of the day that folks are using, in isolation, they're the important thing is to talk about the outputs from these platforms. And so when we talk about the Dynamo platform, we like to do it in the context of the programs that it's producing. 'Cause it doesn't really matter, the fancy tools you have or other capabilities you have, if it's not producing novel drugs, yeah, it. And we like to make sure that they're intertwined and make sure you're seeing how we're using the Dynamo platform to actually create novel molecules. So that's why you'll see it, that story being told through the programs, as we always have. How do you decide whether to advance a genetic disease program forward or oncology program? Yeah, so it's actually- Oncology-centric. So far, it's been oncology-centric. The platform itself is agnostic to therapeutic area, and there are certain targets within genetic disease that have a lot of the same phenotypes of precision oncology targets. So defined patient population that's easily identifiable through biomarker, and that you can get to clinical proof of concept very quickly, and it starts to look like it—they tend to be patient populations that are commercially tractable for companies of our stage and size. And so that the... when we think about new targets to bring forward, whether it's oncology or genetic disease, we're a bit agnostic as to which of the, this, that part of the portfolio that it comes from. Just to be very clear, we've said in the past that we have 7+ unnamed programs. So these targets, these new programs, are just unveiling, you know, some of the, those programs that have been in the unnamed portion of the portfolio. This is not new programs that we've never, that heretofore have never been contemplated within the pipeline. Yeah. Got it. Okay, let's move to 2608. We've seen some data at EORTC-NCI-AACR last year at the triple sort of AACR meeting. You know, at the time, we didn't see any grade 3 or 4 hyperglycemia. But you know, the responses obviously were still sort of on the low side, and you continued to dose. I believe you're not dosing up over 800 at this point. And you've obviously initiated a triple therapy now with fulvestrant and ribo as well as 2608. We're expecting to see an update in the second half of the year. I'm sort of assuming it might be at San Antonio. Is that the timing, and what data can we expect at that time? Yeah, so correct. You know, last August, we gave a bit of an update as to what data we are seeing in the doublets or in combination with fulvestrant at the 600 milligram twice daily dose. We believe that to be an optimal dose. And so we've been focusing on continuing to enroll that doublet regimen. And at JP Morgan earlier this year, we announced that we had fully enrolled our first 20 patients worth of expansion and had expanded that regimen further. And so the goal at the end of the year, you know... Up until now, we've clearly demonstrated clinical proof of mechanism by showing that we can gain mutant selectivity for PI3K alpha, and being able to do that at above the IC80 throughout the dosing interval, and can do that safely in a very differentiated manner from the non-selective inhibitors. The one of the key pieces of key questions left to have answered is, what is the durability of that benefit in being able to have that level of selectivity? Given that the regulatory endpoint here in this patient population is progression-free survival, you know, that is a metric that can only be determined by a robust number of patients and time. We guided to having a disclosure in the back half of this year, and in time, we would have about 40 patients in that, on the doublet regimen, that would have had the opportunity to be on for 6 months or more. The reason why that 6 months or more time point is important is because the two agents with regulatory approval right now have a median PFS in and around 6 months, 5.5 months, 6 months. That's alpelisib and capivasertib. So what we want to be able to do with a robust end is show what the durability of benefit we are seeing from 2608+ fulvestrant, so that in a cross-trial comparison anyways, we can start to see what the PFS potentially could look like against those other regimens. More importantly, you know, give us all the confidence that if we were to move into a phase III here, which we are poised to potentially be able to do, what would be the probability of success? And when you're thinking about response rates, I think so far we saw one out of five, if I remember correctly. What is the relevant bar, and is there even a relevant bar, or is it all about PFS? Yeah, I mean, I think in this, in this disease, in this population, there isn't really a relevant bar. Response rate has not been an approvable endpoint. It's not even been a key secondary endpoint that's been reported out for these other agents. It really is about demonstrating progression-free survival, primarily in this patient population, and then obviously, with, with further, data maturation as development goes on, overall survival becomes something, to look at as well as a key secondary. But response rate, across this disease and across this class has not been a relevant endpoint. Got it. Okay. So what do you think the bar is for you on PFS in order to move to phase III? Yeah. So, you know, I think if you look at the two approved agents, in the, the ER-positive, HER2-negative, PI3K mutant population, you've got alpelisib, the non-selective PI3K alpha inhibitor, from Novartis, and then you've got capivasertib, which is a relatively non-selective AKT inhibitor from AstraZeneca. Capivasertib, based on the most recent numbers we saw from Q1, looks to be taking market share from alpelisib. It looks to be, on a, on a relatively successful launch trajectory. That's an agent that has a 5.5-month progression-free survival in patients post-CDK4/6 inhibitor therapy. That is based on the CAPItello-291 trial subset analysis, retrospectively, of the post-CDK4/6 patients. So it compares, you know, to what you see in the real world with alpelisib, which has been reported to be around 6 months PFS with that agent. You know, I think you're seeing a move towards capivasertib because it does have a reported lower rate of Grade 3 hyperglycemia, of course, comes at the expense of diarrhea and other AEs. But, you know, I think you're seeing some uptake there, again, because of the desire for physicians to avoid hyperglycemia. As you've mentioned, Yaron, you know, as we've disclosed today, with the mutant selective profile of RLY-2608, we've been able to largely dial out the risk of Grade 3 hyperglycemia. And I think what we'd look to be able to be, in a phase III trial would be that 5.5-month benchmark PFS that you've seen for capivasertib. Okay. Do you need to show even... Is it, and what would a phase 3 look like? Is it sort of head-to-head? Is it sort of just, an open label, you know, one-arm study? And do you sort of need to show something a lot better than 6 months, let's say, maybe 6 months-8 months? Yeah, I mean, I think- So- Oh, do you want me to take that? Go ahead. Yeah. Yeah. Yeah, so I think we anticipate, given that both capivasertib and alpelisib have full approvals, in the immediate post-CDK4/6 setting, that likely we would need to run a head-to-head trial, superiority trial against those. That would be one design, that could be considered. You know, I'll preface this by saying that we can't lock down what it would look like until we have more regulatory interaction. But one potential trial that you could imagine would be running a head-to-head superiority trial in combination with fulvestrant and patients following treatment with a CDK4/6 inhibitor. And there, we would look to design a superiority trial, where you're showing that you win both on efficacy, on the superior progression-free survival, that we hope would be a clinically meaningful delta in PFS. And then also win on the safety side, given what we've shown already for 2608, as having a differentiated safety profile compared to either the non-selective PI3K inhibitors or to the profile that we've seen for capivasertib and capmatinib. And so when you're talking about data updating the second half, I mean, we'll be in the second half, you know, in about a month or so. I imagine this would be in a medical meeting typically, or is this gonna be a press release and a company sort of some, you know, webinar? I think no matter what, there will be a company then contextualize the announcement, and then, it is also at a medical meeting. You know, we'll see how integration lines up with abstract timings and whatnot. Would there be any update on June sixth, or is June sixth purely about the next programs? It is fully focused on the next programs, and the plan. Okay. What about timing for the... I guess maybe the next question is, why not test the 800 as a doublet with fulvestrant? Don, you wanna take that? Yeah. So I mean, we have looked at 800 as a doublet with fulvestrant dose escalation. And I think our goal, as we're taking a dose forward, and the goal that's consistent with Project Optimus, is not just identifying, you know, the highest feasible dose that you can take forward, but it's really the optimal dose that balances efficacy and safety. I think we've been very encouraged by the efficacy that we've seen to date for the 600 milligram dose, as we reported last August, you know, with—You mentioned 1 out of 5 responses. Obviously, those data were early, and response rate, as we talked about, is not so relevant. What gets us excited is that we saw, of the 7 patients who had been on for 6 months, we saw 6 of them, who were still continuing therapy without evidence of disease progression. So from the efficacy perspective, you know, I think, again, we've been encouraged with what we see at 600 milligrams. We see good PD, we see good clearance of ctDNA at the 600 milligram dose. We see a highly differentiated safety profile. And I think when you look across all of the spectrum, we think that 600 milligrams reflects what could be an optimal dose to take forward and to be able to maintain patients on treatment for a prolonged period of time. Because this is a patient population where the hope would be, you know, initially in the post-CDK4/6 setting, to see long duration of therapy. But then ultimately, as you move into earlier lines of therapy, to be able to maintain patients on drug for two or even three years in the frontline metastatic setting. So, you know, as we look across all of the data points, we've been very encouraged with 600 milligrams, with just the follow-up on 600 milligrams and enroll more patients. We're also continuing to build a database looking at doses that bracket 600 milligrams as well, to be able to support discussions around dose to take forward into a pivotal trial with FDA. Okay. And so you were still enrolling at the 800, or you did not enroll the 800 as part of the expansion? We do not have an expansion dose cohort. The two expansion doses that we are exploring are 600, which is the main. And then also, as Don alluded to, 400 milligrams- Four hundred -in, in. Yeah. Okay. Okay, and what about the triplet? Maybe give us a sense on the triplet. I assume, again, you are testing the 600, the approved ribo dose and fulvestrant dose, and what's the timing? And maybe tell us about that cohort. Yeah, so the triplet just started early this year. And the goal here is to identify a dose of 2608 that can be combined with the full dose fulvestrant. It's been a challenging regimen to combine with for the non-selective agents. And so the goal throughout the course of this year is to do that: identify a combinable dose of 2608 in the triplet regimen. So the update you'll see towards the end of this year is gonna be very small and likely early, not a lot of follow-up. And again, goal there is to be able to point towards the ability to do what the non-selective inhibitors have not been able to do, safely combine drugs like them. Okay, terrific. Jayna, over to you for FGFR2. Great. Thanks so much. So on lirafugratinib, the RLY-4008, like our other program, you've previously shown data at Triple last year. And based on that data, which is really good, you announced that you'd be pivoting to a tumor-agnostic strategy. Can you remind us why did you choose to pursue tumor-agnostic development instead of your initial approval in FGFR2 naive fusion cholangiocarcinoma, where you already had really strong data with 88% response rate? ... Yeah, you're correct, Jenna. We at the Triple meeting last year, when we disclosed for the first time the tumor-agnostic data, we also said that we would be slowing down our regulatory and commercial effort preparation efforts for cholangiocarcinoma. It was largely due to, you know, as these programs evolve, we've had different legislation come into play, too, namely the IRA, and that is it does not really benefit smaller indications first, and cholangiocarcinoma is a very small, it would be a very small first indication for lirafugratinib. And so therefore, we wanted to really let the tumor-agnostic data catch up and mature and understand the profile in the tumor-agnostic setting. And so we also announced at the meeting we would be minimizing spend against RLY-4008 through 2024, letting the tumor-agnostic data mature further. Then, in the back half of this year, making an update on both data and regulatory path forward for the program, but and bringing that together to kind of discuss more holistic go-forward strategy for the program. And so that, that's what we're on track to be able to do. In the second half of this year, probably after a regulatory interaction, give a bit of a holistic update on the program and where it stands. I think you're on mute, Jayna. Yeah, sorry about that. So yeah, it seems like a lot of things are still up in the air, but so far, kind of based on the data you have, you've seen the best responses so far in fusions. Do you think you're gonna be focusing on that, or are you gonna try to include more than one alteration? Yeah, we'll, we'll follow the data. But, Don, do you wanna talk about where we might - where we priority kind of anticipating? Yeah, I think, I think going in to clinical development with 4008, just based on the history of gene fusions as being strong oncogene drivers, independent of histology, we always anticipated fusions would be among the strongest tumor or the strongest alterations. And I think that's consistent with what we reported at the end of last year, where we saw responses in FGFR2 fusions across multiple different tumor types. And it really does appear to be clearly tumor histology agnostic. We clearly see activity in other alterations as well, including amplifications and mutations. And I think the question there is, do you have the same breadth of activity? Is it truly tumor agnostic, or do you see more tumor dependence? You know, I call out some analysis that we presented last year, for instance, in breast cancer, where in that disease population of the 10 patients with FGFR2 alterations who we treated, we saw good durability, deep responses in four out of the 10. And we were seeing the responses across different alterations, including in mutation and amplification patients. So I'd say today, where the data are pointing us to is, again, the fusions being truly tumor agnostic. I think the question with amplifications and mutations is, there's clearly activity there. Is it the same sort of tumor-agnostic activity, or are those patients potentially addressed in tumor-specific development, for instance, in breast cancer or gastric cancer? Great. So given you mentioned your breast cancer data, given that the data is really good there, are you going to be looking at that separately or as just part of the tumor-agnostic cohort? Yeah, we'll continue to monitor all the data and the potential subsets of... that could provide a path forward from both the development and regulatory standpoint, you know, dependent on how the data and how it matures. But I think the focus of the update in the second half of the year will be really understanding the tumor-agnostic approach, you know, likely to focus on fusions and really understanding both regulatory and the optimal development path forward. Great. And then just could you give us a sense of what it takes to get a tumor-agnostic label? How are you thinking about trial design? Are you enriching for anything like breast cancer? How many tumor types—like, what is the bar in terms of how many tumor types you need and the efficacy you need to see across those tumor types? Don, do you want to take that? That's, that's exactly, those are exactly questions that we need to answer over the course of this year, in discussions with, with health authorities. We can look at the precedent tumor-agnostic approvals and get a feel for what's been acceptable in the past. But I think we'll wanna come back after having discussions with health authorities about the number of patients, distribution of tumor types, agreement that there's unmet medical need in these patients, and, and an understanding of, of what they may be looking for in terms of response rate and follow-up. Just in general, how big do you think the opportunity is for lirafugratinib in kind of these, in, yeah, for lirafugratinib, just in general, now that you've moved on to a tumor-agnostic label? Yeah, so I think, a one reference point is for FGFR2 fusions in the U.S. alone, there's about 13,000 of them per year. And so that is in comparison to FGFR2 fusion cholangiocarcinoma, which is about 800-1,000. So there's definitely a much larger opportunity when you, when you expand outside of just cholangio into the, the tumor-agnostic context. A last final question on lirafugratinib. What can we expect from the regulatory update in the second half of this year? Any update on exactly when that's gonna be, what we're going to get? Yeah, I think it'll be answering some of those questions that you pointed out. Is there a regulatory path forward in the tumor-agnostic setting? In which alteration type? If it requires more development, how much more, what's the number of patients? So it's all the key questions that you highlighted are the ones we anticipate answering in this update in the second half. All right, back to you, Yaron. Well, terrific. I think we're at time, given that we're running sessions in on the 30. So Don and Pete, thanks so much for joining us. We appreciate it. Good to see you, and we'll continue to follow closely. Dave, thank you for having us. Thanks, Yaron. Thank you.